tbuckley/cabot-search huggingface dataset:
HER2CLIMB-05: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer.
Authors: Erika P. Hamilton, Miguel Martin, Ciara Catherine O'Sullivan, Giuseppe Curigliano, Joohyuk Sohn, Junji Tsurutani, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras
Journal: Journal of Clinical Oncology (2023)

TPS1115 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T + P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T + P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T + P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by Blinded Independent Central Review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, Brazil, APAC and EU countries with additional sites planned. Clinical trial information: NCT05132582 .
Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with docetaxel as first-line therapy (1L) for patients (pts) with advanced HER2-positive breast cancer (BC): Updated results from a phase 1b/2 study.
Authors: Xiaojia Wang, Keun Seok Lee, Xiaohua Zeng, Tao Sun, Young-Hyuck Im, Huiping Li, Kun Wang, Huiyan Li, Ping Zhou, Yuanyuan Bao, Zefei Jiang
Journal: Journal of Clinical Oncology (2023)

1044 Background: Despite HER2-targeted agents improving outcomes in HER2-positive (+) BC, some pts develop resistance, relapse, or do not respond to current 1L therapies. Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that binds to two distinct extracellular domains of HER2. Preliminary results from this phase 1b/2 trial (NCT04276493) showed that zani plus docetaxel had a manageable safety profile and demonstrated promising antitumor activity in pts with advanced HER2+ BC; here we present the updated data following enrollment completion. Methods: Cohort 1 of this open-label study is evaluating zani in combination with docetaxel as a 1L therapy in adult females with advanced HER2+ BC who may have received prior neoadjuvant/adjuvant therapy. Cohort 1a pts received zani 30 mg/kg intravenously (IV), Cohort 1b pts received zani 1800 mg IV, both with docetaxel 75 mg/m 2 IV every 3 weeks. The primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR) and disease control rate (DCR). Results: As of Nov 22, 2022, 37 pts (median age 55.0 years [range: 33-80]) were assigned to Cohort 1a (n=10) or 1b (n=27). Median study follow-up was 15.5 months (range: 1.1-29.3); patients received a median of 13 treatment cycles (range 1-37) and 18 (48.6%) pts remained on treatment. Of the 33 efficacy evaluable (EE) pts, confirmed ORR was 90.9% (95% confidence interval [CI]: 75.7, 98.1). Efficacy data are summarized in Table. In total, 36 (97.3%) pts experienced ≥1 treatment-related adverse event (TRAE); 25 (67.6%) pts experienced ≥grade 3 TRAEs. The most common ≥grade 3 TRAEs were decreased neutrophil count, experienced by 18 (48.6%) pts, and decreased white blood cell count, experienced by 7 (18.9%) pts. Serious TRAEs occurred in 6 (16.2%) pts; no TRAEs led to death. Conclusions: Zani combined with docetaxel demonstrated promising antitumor activity as 1L therapy for advanced HER2+ BC, with a manageable safety profile. Clinical trial information: NCT04276493 . [Table: see text]
Use of gender-neutral language in clinical trial protocols in select cancers.
Authors: Garima Gupta, Zin Myint, Donglin Yan, Reema Anil Patel
Journal: Journal of Clinical Oncology (2023)

1574 Background: Around 21% of Generation Z Americans self-identify as lesbian, gay, bisexual, transgender (LGBT), nearly double the proportion of millennials. Despite Affordable Care Act Section 1557 in 2020, transgender individuals continue to have poor access to quality cancer care, including clinical trials. The National Institutes of Health (NIH) recognizes that using gender-neutral language in healthcare is one of many ways to improve sexual and gender minorities (SGM) related health disparities. This study examines use of gender-neutral language in clinical trial protocols in select cancers. Methods: Data was collected from clinicaltrials.gov, a commonly used resource for patients and providers. Phase III clinical trials with all recruitment statuses in the US from 2017 to 2022 were included. Cancer types were limited to those with highest risk of using gender-biased language: breast, ovarian, endometrial, fallopian tube, cervical, prostate, testicular, and penile. For each trial, frequency of use of following terms was recorded by searching under study details section: male, female, she, her, he, his, him, man/men, woman/women, breastfeeding/nursing/lactating/pregnant mother or female or woman. Mean frequency was compared between 2017-19 and 2020-22 using Wilcoxon signed-rank test. Funder type, eligible sex, gender-based eligibility and gender eligibility description were also collected. Data were compared between 2017-19 (pre-1557) and 2020-22 (post-1557) using Fisher exact test. Results: 243 studies were included in the analysis; 130 were pre- and 113 were post-1557. 103/130 (80%) studies between 2017-19 and 78/113 (70%) between 2020-22 included at least one gender-biased term or “male/female” outside of eligible sex description ( p = 0.05), depicting a trend towards improvement; stronger improvement was noted in non-NIH funded studies versus NIH-funded studies. Mean frequency of gender-biased terms was higher in 2017-19 compared to 2020-22 (2.25 vs 1.88, p = 0.02). 27/130 studies (21%) between 2017-19 and 21/113 (19%) of studies between 2020-22 required gender-based eligibility ( p = 0.40). Amongst these, 100% of studies between 2017-19 and 95% of studies between 2020-22 either provided no description or used this clause incorrectly, commenting on sex assigned at birth and not gender identity. This indicates lack of awareness regarding difference between sex assigned at birth and gender identity. While it is evident to investigators during registration on clinicaltrials.gov that eligible sex refers to biological sex, it is not to anyone reviewing the trial for enrollment, resulting in implicit bias. Conclusions: Our study highlights the dire need to address SGM-related health disparities and brings attention towards paucity of gender-neutral language in clinical trial protocols. This step is critical in providing more inclusive care and capturing the rising population of LGBT individuals.
Comparing time to treatment for neoadjuvant chemotherapy for breast cancer across the urban-rural continuum.
Authors: Laura Kasper, Alison Coogan, Rachel Akers, Lilia Lunt, Andrea Madrigrano, Matthew Dixon, Cristina O'Donoghue
Journal: Journal of Clinical Oncology (2023)

e12619 Background: Time-to-treatment is a quality measure in breast cancer care that can impact breast cancer survival as delayed treatment can increase mortality. This study aims to determine whether differences exist in time-to-treatment for breast cancer patients receiving neoadjuvant chemotherapy (NAC) across the urban-rural continuum. Methods: The National Cancer Database (NCDB) was queried for women with a diagnosis of breast cancer between 1 January 2004 – 31 December 2019. Patients who fit criteria for NAC consideration according to NCCN guidelines were included (inflammatory breast cancer, HER2 positive with tumor stage &gt;T1c, triple negative with tumor stage &gt;T1c, HER2 positive or triple negative lymph node positive, and stage III estrogen receptor (ER) positive). Analysis was stratified according to histopathologic subtype and geographic location as defined by the NCDB. Differences were analyzed using χ2 tests. Results: For patients with NAC-eligible breast cancer, there was no statistically significant difference in terms of days until treatment for each histopathologic subtype across the urban-rural continuum. The distance to treatment facility increases the further away patients are from a large metropolitan area, with individuals located in an urban area that is not adjacent to a metro area traveling the furthest distance (12.7mi large metro, 18.1mi small metro, 36.7mi urban adjacent to metro, 62.6mi urban not adjacent to metro, 56.4mi rural). No significant difference in distance traveled was observed between tumor subtype group. Conclusions: While previous studies have determined that rural patients receive NAC at lower rates than those in large urban areas, this study shows that time to treatment and distance traveled is similar across rural urban continuum and different histopathologic subtypes. Future studies are needed to determine why patients receive NAC at lower rates in rural areas.
Neoadjuvant PARP inhibitors in patients with early HER2-negative breast cancer harboring BRCA 1/2 germline mutations: A systematic review and meta-analysis.
Authors: Maria Inez Dacoregio, Maysa Vilbert, Carlos Stecca, Isabella Michelon, Caio Castro, Eitan Amir
Journal: Journal of Clinical Oncology (2023)

e12611 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of germline BRCA mutated (gBRCAm) breast cancer (BC) patients in the adjuvant and metastatic settings. Several studies have explored the role of PARPi in the neoadjuvant setting both with and without chemotherapy. Here, we explore the efficacy and safety of neoadjuvant PARPi in early HER2-negative BC patients. Methods: We searched PubMed, Scopus, and the Cochrane Library databases for randomized (RCT) and non-randomized clinical trials (non-RCT) that reported the proportion of patients with pathological complete response (pCR) after neoadjuvant PARPi and safety. Statistical analysis was performed using R software. Data were pooled using the random effects model. Results: Analysis included 3 RCTs and 4 non-RCTs, with 942 HER-2 negative breast cancer patients, 293 harboring a gBRCA 1/2 mutation. In a pooled analysis, gBRCAm carriers achieved a significantly higher rate of pCR than BRCA wild-type patients (56% versus 37%, p=0.04) with neoadjuvant PARPi. There was no difference in pCR when PARPi were combined with carboplatin (+/- chemotherapy) (40% versus 44%, p=0.69). Among RCTs (n=457) patients received PARPi in combination with either Paclitaxel plus Carboplatin (PCb) (85%) or with Paclitaxel alone (P) (15%). PARPi were associated with a higher pCR which approached, but did not meet statistical significance (51% vs 41%; Odds Ratio [OR]: 1.30, 95%CI 0.97 to 1.74, p=0.08). gBRCAm was associated with higher pCR compared to wild type in RCTs analysis (60% versus 48%; OR: 1.64, 95%CI 1.01 to 2.68, p=0.05). The most common adverse events (AEs) were cytopenias, nausea, fatigue, alopecia, and dizziness. Hematological toxicities were the most frequent serious AEs, including anemia (15%), neutropenia (22%), and thrombocytopenia (3%). The combination of PARPi and carboplatin was associated with higher hematological AEs (78% versus 46%; P=0.002). Conclusions: The addition of PARPi in the neoadjuvant setting improves pCR in early-stage HER2-negative breast cancer and germline BRCA 1/2 mutations, but not for unselected patients. Combination of PARPi with carboplatin does not improve pCR and leads to substantially worse toxicity. Further studies are warranted to identify the best neoadjuvant PARPi schema.[Table: see text]
Effects of ovarian ablation or suppression on breast cancer recurrence and survival: Patient-level meta-analysis of 14,993 pre-menopausal women in 25 randomized trials.
Authors: Richard G. Gray, Rosie Bradley, Jeremy Braybrooke, Mike Clarke, Robert Kerrin Hills, Richard Peto, Jonas C. S. Bergh, Sandra M. Swain, Nancy E. Davidson, Prudence A. Francis, Meredith M. Regan
Journal: Journal of Clinical Oncology (2023)

503 Background: Suppressing ovarian function of women with breast cancer may improve outcome by preventing estrogenic stimulation of any residual cancer, particularly for pre-menopausal women with estrogen receptor (ER)-positive tumors. We report a collaborative meta-analysis of individual participant data from randomized trials of ovarian ablation or suppression. Methods: Data were sought from randomized trials that compared ovarian ablation or suppression versus not. Primary analyses included only premenopausal women age &lt; 55 with ER-positive or unknown tumors, stratified into those who received no chemotherapy, or remained premenopausal following chemotherapy, and those whose menopausal status following chemotherapy was not ascertained. Standard log-rank methods estimated ER-weighted annual event rate ratios (RR). Results: Individual patient data were provided for 25 of 27 relevant trials, comprising 14,993 (98.7%) of 15,195 women randomized. Overall, fewer breast cancer recurrences were seen with ovarian ablation/suppression than control (RR = 0·82, 95%CI 0·77–0·88; p &lt; 0·0001). Recurrence reductions were significantly (p = 0.0003) larger among women (n = 7,213) known to be premenopausal prior to ovarian suppression (RR = 0·70, 0·63–0·78; p = 0·0003) than among those (n = 7,786) whose menopausal status was uncertain after chemotherapy (RR = 0·91, 0·83–0·99; p = 0·03). For known premenopausal women, 15-year risk of recurrence was improved by 12·1% (28·9% vs 41·0%; p &lt; 0·0001. 15-year breast cancer and all-cause mortality were improved by 8·0% (20·9% vs 28·9%; RR 0·69, 0·60–0·80; p &lt; 0·0001) and 7.2% (26·0% vs 33·1%; RR = 0·73, 0·64–0·82; p &lt; 0·0001), respectively, with no increase in deaths without recurrence (RR = 0·88, 0·67–1·14; p = 0·33). Recurrence reductions were significantly (p = 0·003) larger among premenopausal women aged under 45 (RR = 0·63, 0·55–0·72; p &lt; 0·0001) than among those aged 45-54 (RR = 0·84, 0·70–1.00; p = 0·045), but did not differ significantly by other recorded patient or tumor characteristics. Conclusions: For pre-menopausal women aged under 45, ovarian ablation or suppression substantially reduces the 15-year risk of recurrence and death from breast cancer without increasing mortality from other causes.
Association between genomic alterations and response of triple-negative breast cancers (TNBC) to talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy (NACT).
Authors: Hatem Hussein Soliman, Hyo S. Han, Blaise Mooney, Ricardo L Costa, Marie Catherine Lee, Bethany Niell, Alec Chau, Shannon Falcon, Aixa Elena Soyano Muller, Avan J. Armaghani, Nazanin Khakpour, Robert J Weinfurtner, Susan Hoover, John Kiluk, Christine Laronga, Marilin Rosa, Hung T. Khong, Brian J. Czerniecki
Journal: Journal of Clinical Oncology (2023)

598 Background: TVEC is an engineered oncolytic virus (OVs) approved for the treatment of melanoma. We published a phase 1/2 trial combining TVEC with NACT in early stage TNBC demonstrating increased pathologic complete response (pCR) compared to expected rates with NACT. RNAseq was performed on 37 pretreatment samples from enrolled patients to identify potential predictive genomic alterations. Methods: Transcriptomic RNA sequencing analysis was performed on macrodissected tumor tissue through the Moffitt Molecular Genomics core using Illumina Truseq RNA exome kits. Read adapters were detected using BBMerge (v37.88) and removed with cutadapt (v1.8.1). For gene expression analysis, processed raw reads were aligned to human genome HG19 using STAR (v2.5.3a). Gene expression was evaluated as read count at gene level with HTSeq (v0.6.1) and Gencode gene model v19. Gene expression data were normalized and differential expression between experimental groups were evaluated using DEseq2 (v 1.38.2). Ensembl was used for SNP data search. Results: Tumor mutation burden was not significantly different between pCR and non-pCR samples (median 227 vs 222 mut/MB, p = .11). Top 5 upregulated non-immunoglobulin genes associated with pCR in baseline samples were MYBL1, DNAH8, NR2E1, FGFR2, and SLC12A1 (FDR &lt; 1%). A single nucleotide polymorphism (SNP) of the EIF2A gene (c.C290G, p.T97S) was the top variant associated with response present in 21/37 samples (non-pCR = 17/21 vs. pCR = 4/21, FDR = &lt; 1%). This exon 4 coding region SNP is present in 17% of Black, 35% of White, and 46% of Asian individuals but its biologic or clinical significance is unknown. Lower EIF2A pathway activation was associated with inferior response to therapy. Additional data will be presented at the meeting. Conclusions: Genomic alterations including a EIF2A SNP were correlated with response to OV plus NAC in TNBC. EIF2A is an important mediator of cellular responses to OV and may play a role in susceptibility to oncolysis. Additional investigation and validation of these variations in experimental models of OV susceptibility may provide predictive biomarkers for TNBC patients treated with OV plus NAC therapy. Clinical trial information: NCT02779855 .
Time savings from integrating discrete, genomic data into the electronic health record using the Epic Aura Network.
Authors: Leo Posteraro, Patrick Mergler, Dennis Urbanek, Joseff Schulin, Howard Anton, Nancy Kokkinos, James Lin Chen
Journal: Journal of Clinical Oncology (2023)

e13568 Background: The capability to deliver, order, and receive discrete genomics data from external pathology laboratories into the electronic health record (EHR) has improved dramatically. As opposed to unstructured PDF integrations, discrete genomic results allow physicians real-time receipt of results which may trigger rapid clinical actions and expedite patient care. However, these genomic integrations, traditionally point-to-point (P2P), can be time consuming. On the other hand, Epic’s order and results network (Aura) connects pathology labs directly to Epic, which has pre-existing connections to Epic EHR sites. This eliminates the need to create a new connection, and is designed to provide a faster and simpler approach. Tempus was the first vendor to use the Epic genomics module for delivery of discrete, somatic mutational data and now is also the first company to leverage Aura for this purpose. Here, we report on our early Aura integration experiences. Methods: Using the Tempus Database, we retrospectively analyzed medical systems that were all Epic customers and determined their EHR genomic integration time using Aura. Integration time was defined as the time between initial start date of creating “orderables” to time of site testing. The number of EHR medical center analysts was also quantified. We used our prior P2P EHR deployments as a historical control. Results: Six bidirectional Tempus genomic integrations using Aura were performed from July 2022 to December 2022. All medical centers were expansive, multisite hospital systems. Mean number of integrated departments per hospital was 249 (range: 19-699). In 17 P2P integrations prior to Aura, mean integration time was 6.7m (range: 4m-18m). In contrast, mean integration time using Aura over the 6 sites was 1.5m (range: 0.75m-2m), which is a 78% improvement. No correlation was noted between the integration time and number of EHR analysts staffed or departments integrated. The two slowest integration sites (2m and 2.5m) had competing EHR deployment priorities. Conclusions: Using Aura, the speed of Tempus EHR integration was improved by 78% for bidirectional, discrete genomic data. Dedicated EHR integration resourcing reduced deployment times to as low as 3 weeks. This reduction in integration time may further the adoption of genomic EHR integrations and improve patient care by expediting time to appropriate, targeted treatments.